Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
  • C07D501/02—Preparation
  • C07D501/08—Preparation by forming the ring or condensed ring systems
  • C07D501/10—Preparation by forming the ring or condensed ring systems from compounds containing the penicillin ring system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
  • C07D501/14—Compounds having a nitrogen atom directly attached in position 7

Definitions

• This invention relates to novel cephalosporin type antibiotics and methods for producing the same. More particularly, the present invention relates to novel 7-acylamido-3-halo-3-methyl-cepham-4-carboxylic acids and esters thereof. The present invention also relates to a method for producing 7-acylamido-3-halo-3-methyl-cepham-4-carboxylic acids and esters thereof.
• R 1 represents benzyl or phenoxymethyl radical
• R 2 represents hydrogen atom, alkyl, benzyl, p-nitrobenzyl or 2,2,2-trichloroethyl radical
• X represents a halogen atom
• the object compounds of this invention are not only novel cephalosporin antibiotics having antibiotic property per se but also novel useful compounds as intermediates for the preparation of several kinds of cephalosporin type antibiotics.
• Example 13 when these compounds are subjected to dehydrohalogenation by use of a base and then to hydrolysis, the corresponding 7-acylamido-3-methyl- ⁇ 3 -cephem-4-carboxylic acids which are known as useful cephalosporin antibiotics per se can be obtained.
• These compounds can be also used as intermediates to give more useful cephalosporin antibiotics, for example, cephalexin. More particularly, the cephalexin can be obtained from the above 7-acylamido-3-methyl- ⁇ 3 -cephem-4-carboxylic acid by a known method, for example, the method which is described in the specification of patent publication (Laid Open No.
• This invention relates especially to a process for the preparation of a 7-acylamido-3-halo-3-methyl-cepham-4-carboxylic acid esters having the general formula; ##SPC2##
• R 1 represents a benzyl or phenoxymethyl radical
• R 2 represents an alkyl, benzyl, p-nitrobenzyl or 2,2,2-trichloroethyl radical
• X represents a halogen atom, which comprises the reaction of a penicillin sulfoxide ester having the general formula: ##SPC3##
• M represents a metal atom
• n is an integer of 1 to 5
• X is a halogen atom
• this invention relates especially to a 7-acylamido-3-halo-3 -methyl-cepham-4-carboxylic acid derivative having the general formula: ##SPC4##
• R 1 and X are the same as above, which comprises the reaction of a penicillin sulfoxide ester having the general formula: ##SPC5##
• R 1 is the same as above, and R 3 represents benzyl, p-nitrobenzyl or 2,2,2-trichloroethyl radical, with a metal halide having the general formula:
• This compound is a peculiar cephalosporin type compound having a halogen atom in its cepham nucleus, and inhibits strongly the growth of gram-positive organisms in the form of an acid.
• the starting material, the 6-acylamidopenicillanic acid sulfoxide ester may be easily prepared from penicillin V, penicillin G or 6-aminopenicillanic acid.
• the reaction of the starting material, 6-acylamido-penicillanic acid sulfoxide ester with the metal halide is carried out in an inert solvent by heating at 70° - 130°C.
• a zinc halide, stannous halide and mercuric halide may be referred to as being useful.
• Stannous chloride, bromide and iodide, zinc chloride, and mercuric chloride are particularly preferable.
• halo-substituted cepham carboxylic acid ester having the halogen atom corresponding to a used metal halide may be obtained.
• the amount of the metal halide used is practically, 1.0-2.0 mol per one mol of the starting material, 7-acylamidopenicillanic acid sulfoxide ester.
• An inert solvent used in the reaction is a solvent which easily dissolves the metal halides, and a purified dioxane is preferable.
• the reaction may be accomplished in dioxane by heating with refluxing for 4 - 6 hours or by heating at 85° - 95°C for 7 - 10 hours.
• the separation of a resulting compound from the reaction mixture may be carried out by usual methods to be applied in chemical synthesis, for example, column chromatography.
• column chromatography In applying elution column chromatography using 30 - 50 parts by weight of silica gel (100 - 200 mesh) per one part by weight of the reactant and elution solvent consisting of a mixed solvent of benzene-ethyl acetate having a volume ratio of 10:1 - 1:1, the resultant may be separated into respective elute portions.
• the elute portions containing a 7-acylamido-3-halomethyl-cepham-4-carboxylic acid ester having the general formula (II) as principal resultant may be easily detected by a detecting test reaction for halogen-containing compounds, for example, Beilstein copper wire reaction test or thin-layer layer chromatography.
• a detecting test reaction for halogen-containing compounds for example, Beilstein copper wire reaction test or thin-layer layer chromatography.
• esters of 7-acylamido-3-halo-3-methyl-cepham-4-carboxylic acid yield novel cephalosporin antibiotics having the above general formula (III) through deesterification thereof.
• esters of 7-acylamido-3-halo-3-methyl-cepham-4-carboxylic acid give easily desacetoxycephalosporanic acid derivatives by dehydrohalogenation thereof, which is as follows: ##SPC7##p1 wherein R 1 , R 2 and X are the same as above.
• halo-cepham compounds having the general formula (II) are dehydrohalogenated when heated in acetone with alkaline carbonate or reacted in benzene with trialkylamine or pyridine base, and give desacetoxycephalosporanic acid ester in good yield.
• the compounds having the formula (IV) are intermediates for the preparation of desacetoxycephalosporin type antibiotics which are represented by cephalexin. Therefore, esters of 7-acylamido-3-halo-3-methyl-cepham-4-carboxylic acid are also important intermediates for these antibiotics.
• esters of 7-acylamido-3-methyl-cepham-4-carboxylic acid and suitable conditions for elimination reaction thereof are chosen, these esters may be decomposed and converted to the free acid thereof without receiving considerable effect to the cepham ring thereof.
• 7-phenoxyacetoamido-3-chloro-3-methyl-cepham-4-carboxylic acid benzyl (or substituted benzyl) ester is subjected to catalytic reduction using palladium-active carbon catalysis or 2,2,2-trichloroethyl ester of the said carboxylic acid is subjected to decomposition using zinc dust with acetic acid, both of them give 7-phenoxyacetoamido-3-chloro-3-methyl-cepham-4-carboxylic acid.
• the said 7-phenoxyacetoamido-3-chloro-3-methyl-cepham-4-carboxylic acid inhibits the growth of Staphylococcus.aureus 209 P strain in a concentration of 12.5
• a mixed solvent of benzene-ethyl acetate (4:1) was used as elution solvent and the elute solution was collected in every 10 ml portion. Each portion was subjected to thin-layer chromatography and the portions containing the similar ingredient to each other are combined. The portions of Nos. 49 - 60 were concentrated. After a small amount of methanol is added thereto, the residue crystallized to give 0.24 g of 7-phenoxyacetoamido- ⁇ 3 -cephem-4-carboxylic acid ethylester as colourless needles having mp. 138.5° - 139.5°C (yield 7%). Also the elute portions of Nos.
• the absorbing silica gel thus obtained was put on the top of a column consisting of 150 g of silica gel and was subjected to elution with a mixed solvent of benzene-ethyl acetate (4:1). The elute was collected in every 25 g portion. Each portion was subjected to thin-layer chromatography to detect the eluted ingredient. The elute portions Nos. 15 - 18 were made together and distilled under reduced pressure to give 0.50 g of 7-phenoxyacetoamido-3-methyl- ⁇ 3 -cephem-4-carboxylic acid p-nitrobenzylesters crystals having mp. 189° - 191°C.
• the ethyl acetate was distilled off under reduced pressure and the residue was purified by column chromatography using 120 g of silica gel (100 - 200 mesh) and a mixed solvent of benzene-ethyl acetate (4:1). The elute was collected in portions and concentrated. After making together the portions which gave a positive Beilstein copper wire test and in which only a single ingredient was found by thin-layer chromatography, the resultant was treated in the same manner as described above. There was obtained 2.70 g of colourless oily 7-phenoxyacetoamido-3-iodo-3-methyl-cepham-4-carboxylic acid methylester.

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• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Biotechnology (AREA)
• Molecular Biology (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Pharmacology & Pharmacy (AREA)
• Oncology (AREA)
• General Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Communicable Diseases (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Medicinal Chemistry (AREA)
• Cephalosporin Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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Cited By (9)

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Citations (5)

• 1972
  • 1972-04-14 JP JP3685072A patent/JPS551272B2/ja not_active Expired
• 1973
  • 1973-04-10 GB GB1705373A patent/GB1377899A/en not_active Expired
  • 1973-04-11 US US05/350,199 patent/US3963712A/en not_active Expired - Lifetime
  • 1973-04-13 DE DE2318852A patent/DE2318852C3/de not_active Expired

Patent Citations (5)

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